PAX-3 AND THE REGULATION OF SOMITIC MYOGENESIS

Harvard University (Medical School), Boston MA

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Abstract

DESCRIPTION: The central goal of this proposal is to understand how signals from surrounding tissues activate somite myogenesis. Although it is clear that expression of either MyoD or Myf-5 is essential for the formation of skeletal muscle, it has hitherto been unclear how these genes are activated during development. The PI has begun to address what regulatory molecules mediate the induction of MyoD and Myf-5 by signals from either the axial tissues (i.e., the neural tube/notochord) or the overlying ectoderm. He has found that the muscle promoting signals from the axial tissues can be mimicked by in vitro supplied Wnt and Shh signals. Furthermore, he has found that signals from either the overlying ectoderm or in vitro supplied Wnt and Shh signals can induce somitic expression of the paired box transcription factors, Pax-3 and Pax-7, concomitant with expression of Myf-5 and prior to that of MyoD. Moreover, infection of somites in vitro with a retrovirus encoding Pax-3 (which is normally expressed in the dermomyotome) is sufficient to induce expression of MyoD, Myf-5 and myogenin in paraxial mesoderm in the absence of inducing tissues. This finding has led the PI to speculate that the muscle-promoting signals from the axial tissues, the overlying ectoderm or in vitro supplied Wnt and Shh signals may activate somitic myogenesis via a Pax-3 dependent pathway. The focus of this proposal is to elucidate how Pax-3 activates myogenic bHLH gene expression in the somite. Pax-3 is the first identified transcription factor shown to be capable of activating the expression of MyoD and Myf-5 in somitic tissue. The major goals of this grant are focused on determining how Pax-3 activates myogenic bHLH gene expression and how this activity of Pax-3 is modulated. The goals are: 1. Determine if Pax-7 and/or an alternatively spliced isoform of Pax-3 activate somitic myogenesis. 2. Determine if MyoD and Myf-5 expression are directly or indirectly activated by Pax-3. 3. Identify somitic genes whose expression is positively or negatively regulated by Pax-3. 4. Determine how the muscle promoting activity of endogenous Pax-3 is blocked in the neural tube.